Knockout of Ceramide Kinase Aggravates Pathological and Lethal Responses in Mice with Experimental Colitis.

Sphingolipids and their metabolic enzymes are implicated in ulcerative colitis. Ceramide kinase (CerK) catalyzes the phosphorylation of ceramide to ceramide-1-phosphate (C1P). Previous studies showed the activation of CerK by the pro-inflammatory cytokine interleukin-1β, the C1P-induced up-regulation of prostanoids exerting protective effects against colitis, and the C1P-induced down-regulation of the pro-inflammatory cytokine tumor necrosis factor-α. In order to elucidate CerK/C1P functions in colitis, we examined the severity of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) and CerK deletion (CerK(-/-)) mice. Lethal responses were observed in C57BL/6 mice treated with DSS in dose- and time-dependent manners. The depletion of CerK enhanced DSS-induced lethal responses without affecting the onset of these responses. In colons from mice treated with 2.5% DSS for 10 d, epithelial damage was significantly enhanced by the depletion of CerK by day 5, whereas decreases in occluding and E-cadherin levels were similar in both mice. On day 5, the DSS treatment increased spleen weights and colonic levels of cyclooxygenase-2, but not cytosolic phospholipase A2α, and induced a contractile dysfunction in the colons of both mice. The DSS-induced increase in the damage activity index score between days 5 and 10 was slightly enhanced and the decrease in this score from day 10 was slower in CerK(-/-) mice than in WT mice. On day 7 after the DSS treatment, spleen weights slightly decreased and increased in WT and CerK(-/-) mice, respectively. These results indicate that the depletion of CerK enhances the pathology of colitis and lethal responses in DSS-treated mice.

[1]  Zhongyin Zhou,et al.  Therapeutic effect of imiquimod on dextran sulfate sodium-induced ulcerative colitis in mice , 2017, PloS one.

[2]  Yong-Moon Lee,et al.  Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability , 2017, Journal of cellular and molecular medicine.

[3]  S. Uppugunduri,et al.  Uridine Ameliorates Dextran Sulfate Sodium (DSS)-Induced Colitis in Mice , 2017, Scientific Reports.

[4]  T. Kosaka,et al.  Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis‐associated colon cancer , 2017, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  B. Brüne,et al.  Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity , 2017, Cellular and Molecular Life Sciences.

[6]  S. Vermeire,et al.  Novel Targeted Therapies for Inflammatory Bowel Disease. , 2017, Trends in pharmacological sciences.

[7]  A. Nusrat,et al.  Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. , 2016, Gastroenterology.

[8]  R. Fan,et al.  Correction: mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile , 2016, PloS one.

[9]  T. Kim,et al.  Long-Term Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Dextran Sulfate Sodium-Induced Murine Chronic Colitis , 2016, Gut and liver.

[10]  A. Gomez-Muñoz,et al.  Regulation of cell migration and inflammation by ceramide 1-phosphate. , 2016, Biochimica et biophysica acta.

[11]  M. Maceyka,et al.  Sphingosine‐1‐phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  Y. Hannun,et al.  Alkaline ceramidase 3 deficiency aggravates colitis and colitis-associated tumorigenesis in mice by hyperactivating the innate immune system , 2016, Cell Death and Disease.

[13]  J. Saba,et al.  Sphingosine-1-phosphate in inflammatory bowel disease and colitis-associated colon cancer: the fat's in the fire. , 2015, Translational cancer research.

[14]  Yong-Moon Lee,et al.  Altering sphingolipid composition with aging induces contractile dysfunction of gastric smooth muscle via KC a1.1 upregulation , 2015, Aging cell.

[15]  Y. Hannun,et al.  Distinct Roles for Hematopoietic and Extra-Hematopoietic Sphingosine Kinase-1 in Inflammatory Bowel Disease , 2014, PloS one.

[16]  P. D. de Jong,et al.  Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. , 2014, The Journal of clinical investigation.

[17]  Sarah Spiegel,et al.  Sphingolipid metabolites in inflammatory disease , 2014, Nature.

[18]  P. Sarlós,et al.  Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility. , 2014, World journal of gastroenterology.

[19]  Y. Hannun,et al.  Loss of neutral ceramidase increases inflammation in a mouse model of inflammatory bowel disease. , 2012, Prostaglandins & other lipid mediators.

[20]  M. Perše,et al.  Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks , 2012, Journal of biomedicine & biotechnology.

[21]  C. Chalfant,et al.  Ceramide Kinase Regulates the Production of Tumor Necrosis Factor α (TNFα) via Inhibition of TNFα-converting Enzyme* , 2011, The Journal of Biological Chemistry.

[22]  K. Chadee,et al.  Tumor Necrosis Factor-α and Muc2 Mucin Play Major Roles in Disease Onset and Progression in Dextran Sodium Sulphate-Induced Colitis , 2011, PloS one.

[23]  T. Mizushima,et al.  Therapeutic Effects of Novel Sphingosine-1-Phosphate Receptor Agonist W-061 in Murine DSS Colitis , 2011, PloS one.

[24]  H. Sugihara,et al.  Increased apoptosis and decreased proliferation of colonic epithelium in dextran sulfate sodium-induced colitis in mice. , 2010, Oncology reports.

[25]  A. Billich,et al.  Ovalbumin-induced plasma interleukin-4 levels are reduced in ceramide kinase-deficient DO11.10 RAG1-/- mice , 2010, Lipids in Health and Disease.

[26]  C. Hofmann,et al.  Lipid Alterations in Experimental Murine Colitis: Role of Ceramide and Imipramine for Matrix Metalloproteinase-1 Expression , 2009, PloS one.

[27]  F. Bornancin,et al.  Ceramide kinase deficiency impairs microendothelial cell angiogenesis in vitro. , 2009, Microvascular research.

[28]  N. Gray,et al.  Modulation of TNFalpha, IL-10 and IL-12p40 levels by a ceramide-1-phosphate analog, PCERA-1, in vivo and ex vivo in primary macrophages. , 2009, Immunology letters.

[29]  K. Isobe,et al.  Thymic Involution Correlates with Severe Ulcerative Colitis Induced by Oral Administration of Dextran Sulphate Sodium in C57BL/6 Mice but not in BALB/c Mice , 2008, Inflammation.

[30]  Y. Igarashi,et al.  Role of ceramide kinase in peroxisome proliferator‐activated receptor beta‐induced cell survival of mouse keratinocytes , 2008, The FEBS journal.

[31]  Y. Zhuang,et al.  Suppression of Ulcerative Colitis in Mice by Orally Available Inhibitors of Sphingosine Kinase , 2008, Digestive Diseases and Sciences.

[32]  Y. Igarashi,et al.  The generation and behavioral analysis of ceramide kinase-null mice, indicating a function in cerebellar Purkinje cells. , 2007, Biochemical and biophysical research communications.

[33]  W. Stenson.  Prostaglandins and epithelial response to injury , 2007, Current opinion in gastroenterology.

[34]  L. Wheeler,et al.  The Prevention of Colitis by E Prostanoid Receptor 4 Agonist through Enhancement of Epithelium Survival and Regeneration , 2007, Journal of Pharmacology and Experimental Therapeutics.

[35]  O. Inatomi,et al.  The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice. , 2006, Oncology reports.

[36]  Hiroyuki Nakamura,et al.  Ceramide-1-phosphate activates cytosolic phospholipase A2alpha directly and by PKC pathway. , 2006, Biochemical pharmacology.

[37]  Ruslan Medzhitov,et al.  Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis , 2004, Cell.

[38]  C. Leslie,et al.  Ceramide 1-Phosphate Is a Direct Activator of Cytosolic Phospholipase A2* , 2004, Journal of Biological Chemistry.

[39]  A. Bielawska,et al.  Ceramide Kinase Mediates Cytokine- and Calcium Ionophore-induced Arachidonic Acid Release* , 2003, Journal of Biological Chemistry.

[40]  U. Sohn,et al.  C2-ceramide-induced circular smooth muscle cell contraction involves PKC-ε and p44/p42 MAPK activation in cat oesophagus , 2002 .

[41]  S. Spiegel,et al.  Ceramide Kinase, a Novel Lipid Kinase , 2002, The Journal of Biological Chemistry.

[42]  Judy H. Cho,et al.  Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice. , 2001, The Journal of clinical investigation.

[43]  Sasaki,et al.  Inhibition of dextran sulphate sodium (DSS)‐induced colitis in mice by intracolonically administered antibodies against adhesion molecules (endothelial leucocyte adhesion molecule‐1 (ELAM‐1) or intercellular adhesion molecule‐1 (ICAM‐1)) , 1999, Clinical and experimental immunology.

[44]  L. Eckmann,et al.  Amendment history : Corrigendum ( April 2005 ) Toll-like receptor 9 – induced type I IFN protects mice from experimental colitis , 2018 .

[45]  L. Obeid,et al.  Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis. , 2017, Advances in biological regulation.

[46]  Kenjiro Matsumoto,et al.  Neurogenic contraction of mouse rectum via the cyclooxygenase pathway: Changes of PGE2-induced contraction with dextran sulfate sodium-induced colitis. , 2010, Pharmacological research.